Compounds which enhance the neurotransmission of serotonin (5-HT) are known to be useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological means which caused them to possess numerous undesired side effects. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients (see e.g., LePoul et al., Arch. Pharmacol., 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al., Trends Neurosci., 19:378-383 (1996) suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
U.S. Pat. No. 3,058,980 discloses the preparation of compounds of the following formula which are known to exhibit analgesic activity. ##STR2##
WO 8907596-A discloses the preparation of compounds having the following formula which are active in a variety of CNS disorders, including depression and schizophrenia. ##STR3##
U.S. Pat. No. 4,612,312 discloses compounds of the following formula as anxiolytic and antihypertensive agents. ##STR4##